A Macrophage-Pericyte Axis Directs Tissue Restoration via Amphiregulin-Induced Transforming Growth Factor Beta Activation

Immunity. 2019 Mar 19;50(3):645-654.e6. doi: 10.1016/j.immuni.2019.01.008. Epub 2019 Feb 12.


The epidermal growth factor receptor ligand Amphiregulin has a well-documented role in the restoration of tissue homeostasis after injury; however, the mechanism by which Amphiregulin contributes to wound repair remains unknown. Here we show that Amphiregulin functioned by releasing bioactive transforming growth factor beta (TGF-β) from latent complexes via integrin-αV activation. Using acute injury models in two different tissues, we found that by inducing TGF-β activation on mesenchymal stromal cells (pericytes), Amphiregulin induced their differentiation into myofibroblasts, thereby selectively contributing to the restoration of vascular barrier function within injured tissue. Furthermore, we identified macrophages as a critical source of Amphiregulin, revealing a direct effector mechanism by which these cells contribute to tissue restoration after acute injury. Combined, these observations expose a so far under-appreciated mechanism of how cells of the immune system selectively control the differentiation of tissue progenitor cells during tissue repair and inflammation.

Keywords: Amphiregulin; Macrophages; TGFb; pericytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amphiregulin / metabolism*
  • Animals
  • Cell Differentiation / physiology
  • Female
  • Macrophages / metabolism*
  • Male
  • Mesenchymal Stem Cells / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Myofibroblasts / metabolism
  • Pericytes / metabolism*
  • Transforming Growth Factor beta / metabolism*


  • Amphiregulin
  • Transforming Growth Factor beta